Overexpression of 15-Lipoxygenase in Vascular Endothelium Accelerates Early Atherosclerosis in LDL Receptor–Deficient Mice

Abstract

Abstract-To study the possible role of the human lipid-oxidizing enzyme 15-lipoxygenase (15-LO) in atherosclerosis, we overexpressed it specifically in the vascular wall of C57B6/SJL mice by using the murine preproendothelin-1 promoter. The mice overexpressing 15-LO were crossbred with low density lipoprotein (LDL) receptor-deficient mice to investigate atherogenesis. High levels of 15-LO were expressed in the atherosclerotic lesion in the double-transgenic mice as assessed by immunohistochemistry. The double-transgenic, 15-LO-overexpressing, LDL receptor-deficient mice (LDLR Ϫ/Ϫ /15LO) developed significantly larger atherosclerotic lesions at the aortic sinus compared with lesions in the LDL receptor-deficient (LDLR Ϫ/Ϫ ) mice after 3 and 6 weeks (107 000 versus 28 000 m 2 [PϽ0.001] and 121 000 versus 87 000 m 2 [PϽ0.05], respectively) of an atherogenic diet. LDL from the LDLR Ϫ/Ϫ /15LO mice was more susceptible to oxidation than was the LDL from the control LDLR Ϫ/Ϫ mice, as shown by a shorter lag period for copper-induced conjugated diene formation. On the other hand, no differences were found in the levels of serum anti-oxidized LDL antibodies between the study groups. There were also no differences with respect to the density of macrophages and T lymphocytes infiltrating the lesions in both experimental groups. Taken together, these results support the hypothesis that 15-LO overexpression in the vessel wall is associated with enhanced atherogenesis.

Critical Role of Macrophage 12/15-Lipoxygenase for Atherosclerosis in Apolipoprotein E–Deficient Mice

“…10 -12 A variety of vascular cells are able to express 12/15-LO, including endothelial cells, 13,14 smooth muscle cells, 13,14 and monocytes/macrophages. 13,15 Overexpression of 12/15-LO in mouse endothelial cells 16 and rabbit monocytes/macrophages 17 resulted in completely opposite effects: The former was proatherogenic and the latter antiatherogenic, which indicates a possibility that different cellular expression of 12/15-LO may have different effects on atherosclerosis or that species differences may exist.…”

Src-dependent STAT-3-mediated Expression of Monocyte Chemoattractant Protein-1 Is Required for 15(S)-Hydroxyeicosatetraenoic Acid-induced Vascular Smooth Muscle Cell Migration

“…It is also known that 15-LOX1 and 12/15-LOX are involved in the oxidation of low density lipoprotein, a contributing factor in the pathogenesis of atherosclerosis (15, 16). Furthermore, using either transgenic or knock-out mice models, a number of studies have demonstrated that 15-LOX1 and its murine ortholog 12/15-LOX play a role in atherosclerosis and restenosis (17)(18)(19). In addition, human atheroma homogenates upon incubation with AA converted it mainly to .…”

Baicalein is a potent in vitro inhibitor against both reticulocyte 15-human and platelet 12-human lipoxygenases

“…2,3 There are three major human LOs (hLOs), 5-, 12-, and 15-hLO, whose main difference is the position of dioxygen incorporation into arachidonic acid (AA) (C-5, C-12, or C-15). 4,5 These three hLO isozymes are of great interest to scientists because they have been shown to be involved in a variety of diseases; 5-hLO in prostate cancer 6,7 and asthma 8 , 12-hLO in immune disorders 9 and breast cancer 7,10,11 , and 15-hLO-1 in atherosclerosis 12 and colorectal cancer. 7,13 Due to their involvement in such diseases, a better understanding of the mode of inhibition of small molecules is necessary to aid in future rational drug design against specific LO isozymes.…”